Glatiramer acetate: long-term safety and efficacy in relapsing-remitting multiple sclerosis

Abstract

Glatiramer acetate (GA) is approved for relapsing-remitting multiple sclerosis in 57 countries worldwide, with more than 2 million patient-years of exposure and over 20 years of continuous clinical use without new safety concerns. GA has an overall favorable risk–benefit profile: 30% reduced annual relapse rate and decreased brain lesion activity. In clinically definite MS or clinically isolated syndrome, GA slows brain atrophy, which may be related to its unique anti-inflammatory and neuroprotective mechanisms of action. Early treatment with GA delays the onset of clinically definite MS more effectively than late treatment in clinically isolated syndrome. GA is not associated with immunosuppression, autoimmune disease, infections or development of neutralizing antibodies. A new three-times-weekly formulation of GA is available to potentially reduce the incidence of injection-related side effects. Other safety advantages of GA include its pregnancy rating (Category B) and limited uncontrolled data suggesting that tolerability is similar in children with MS.

Keywords:

• clinically isolated syndrome
• disease-modifying therapy
• glatiramer acetate
• multiple sclerosis
• relapsing-remitting multiple sclerosis

Financial & competing interests disclosure

Editorial and writing assistance were provided by M Bialek and NC Stilwell of Connexion Healthcare (Newtown, PA, USA). Teva Pharmaceutical Industries provided financial support for these services. AL Boster received compensation for advisory board participation from Biogen Idec, Genzyme, Medtronic, Novartis and Teva; received honoraria for lecturing from Novartis; received research funding for participation in trials from Actelion, Biogen Idec, Jazz, Mallinckrodt, NIH, Roche and Sun Pharma; received compensation for a CME program from Peerview. CC Ford has been engaged in consulting meetings with medical divisions of Biogen Idec, Novartis, Roche-Genentech and Teva Neuroscience; active multicenter research projects with Biogen Idec, MedImmune, Merck-Serono, Novartis, Roche-Genentech, Teva Neuroscience, Ono and Genzyme. O Neudorfer is an employee of Teva Pharmaceuticals. Y Gilgun-Sherki was an employee of Teva Pharmaceuticals at the time that he co-authored the manuscript but is no longer employed by Teva Pharmaceuticals. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Key issues

• Glatiramer acetate (GA) has been continuously administered for more than 20 years to patients with relapsing-remitting multiple sclerosis (RRMS) as their sole disease-modifying therapy (DMT), resulting in minimal disability progression in this subset of patients.

• Used extensively worldwide, with approval in 57 countries, GA continues to be registered in new markets and territories globally on an ongoing basis.

• GA is administered as an injection, and it continues to be a first-line treatment in MS-treatment algorithms throughout the world because of its favorable risk–benefit profile and high adherence rates.

• GA was found to be efficacious in reducing relapse rates in clinically isolated syndrome, as well as in RRMS, and it could potentially be effective in other immune-mediated diseases.

• GA is generally well tolerated and safe and has accumulated more than 2 million patient-years of exposure, with very few significant adverse events; the most common treatment-emergent adverse events are injection-site reactions, which are generally transient and resolve without treatment or clinical sequelae.

• GA has numerous safety advantages over other treatments for RRMS: it has not been associated with immunosuppression, autoimmune disease, infections or the development of neutralizing antibodies, which can have an adverse impact on long-term efficacy of other DMTs. GA also has a pregnancy risk Category B rating, and limited uncontrolled data suggest that tolerability of GA is similar in children and adults with MS.

• Because of the favorable risk–benefit profile of GA, it can be administrated as monotherapy to treatment-naïve RRMS patients, as an alternative treatment for patients who cannot tolerate other DMTs (i.e., IFN-β products), or potentially as part of a combination therapy.

• GA has a unique mechanism of action that may be associated with the high number of potential polypeptide epitopes. GA induces a broad immunomodulatory effect that includes competition for major histocompatibility complex binding; antagonism at specific T-cell receptors; biases of dendritic cells, monocytes and B cells toward anti-inflammatory responses; induction of Th2/3 and Treg and downregulation of Th1 and Th17 cells. In addition, GA treatment generates neuroprotective repair consequences, such as secretion of neurotrophic factors, reduced myelin and neuroaxonal damage and remyelination and neurogenesis in animal models.

Notes